A specialized integrin-binding motif enables proTGF-β2 activation by integrin αVβ6 but not αVβ8.
X-ray crystallography
integrins
transforming growth factor beta
TGFb2
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
13 06 2023
13 06 2023
Historique:
medline:
8
6
2023
pubmed:
6
6
2023
entrez:
6
6
2023
Statut:
ppublish
Résumé
Activation of latent transforming growth factor (TGF)-β2 is incompletely understood. Unlike TGF-β1 and β3, the TGF-β2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-β2 contains a related but divergent 13-residue integrin-recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin αVβ6 but not αVβ8. Both classes of motifs compete for the same binding site in αVβ6. Multiple changes in the longer motif underlie its specificity. ProTGF-β2 structures define interesting differences from proTGF-β1 and the structural context for activation by αVβ6. Some integrin-independent activation is also seen for proTGF-β2 and even more so for proTGF-β3. Our findings have important implications for therapeutics to αVβ6 in clinical trials for fibrosis, in which inhibition of TGF-β2 activation has not been anticipated.
Identifiants
pubmed: 37279271
doi: 10.1073/pnas.2304874120
pmc: PMC10268255
doi:
Substances chimiques
integrin alphavbeta6
0
Transforming Growth Factor beta2
0
Integrins
0
Transforming Growth Factor beta1
0
Antigens, Neoplasm
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2304874120Subventions
Organisme : NIGMS NIH HHS
ID : P30 GM133893
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159714
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM138396
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK124443
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007527
Pays : United States
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